Tumor necrosis factor (TNF), a naturally occurring cytokine, plays a central role in the inflammatory response and in immune injury. TNF is formed by the cleavage of a precursor transmembrane protein, forming soluble molecules, which aggregate to form trimolecular complexes. These complexes bind to receptors found on a variety of cells. The binding of TNF causes many pro-inflammatory effects, including release of other pro-inflammatory cytokines, such as interleukin IL-6, IL-8, and IL-1; release of matrix metalloproteinases; and upregulation of the expression of endothelial adhesion molecules, further amplifying the inflammatory and immune cascade by attracting leukocytes into extravascular tissues. TNF was found to have a main role in the pathogenesis of several immune mediated disorders, among them rheumatoid arthritis (RA) and Crohn's Disease. TNF alpha may have a role in the gut in various local inflammatory and infectious disorders. It is known that high levels of the pro-inflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), are present in the gut mucosa of patients suffering form various diseases, in particularly inflammatory bowel diseases (IBD).
Specific TNF inhibitors/antagonists were developed, such as infliximab, a chimeric anti-TNF monoclonal antibody (mAb), which showed significant effect in treating Crohn's Disease and RA, as well as etanercept, a recombinant fusion protein consisting of two soluble TNF receptors joined by the Fc fragment of a human IgG1 molecule, which was found effective in the treatment of treating RA and psoriatic Arthritis. Other TNF blockers are pegylated soluble TNF Receptor Type I (PEGs TNF-R1), other agents containing soluble TNF receptors, CDP571 (a humanized monoclonal anti-TNF-alpha antibodies), thalidomide, phosphodiesterase 4 (IV) inhibitor thalidomide analogues and other phosphodiesterase IV inhibitors.
This therapeutic potential of TNF antagonists and anti TNF alpha receptor is based on the fact that TNF-alpha is the main mediator of the inflammatory response in many organ systems.
Various researches showed that all TNF inhibitors are immunosuppresssants.
Parenterally administered soluble anti TNF alpha receptor is being used or was tested in the treatment of various TNF dependent inflammatory disorders, such as stomatitis, rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. Further the effect of TNF antagonists was assessed in the the following diseases/conditions: demyelinating diseases, neurodegenerative diseases, trauma, injuries and the like.
Oral administration, which is non-invasive, provides many advantages: ease and convenience of use, improved patient acceptance and compliance, high degree of vascularization, relatively lengthy retention time, natural disposal of inactive, non-metabolized ingredients, direct contact with the gastrointestinal organs.
Oral administration of anti TNF or of the TNF receptor fusion protein also carries an advantage of using the unique ability of the immune system of the gut to induce regulatory T-Cells (Tregs) or to alter the systemic immune system in specific ways that are different and more effective than by intravenous administration. In addition, oral administration may alter the systemic immune paradigm suppressing inflammation without exposing the patient to a general immune suppression and therefore to severe infections or malignancies that are known to be associated with the intravenous route of treatment of anti TNF compounds.
Currently, there is no oral TNF antagonist or anti TNF alpha receptor in the market due to the high acidity and enzymatic degradation in the stomach that inactivates or destroys the molecule before reaching the blood circulation.
There is a need for an oral composition comprising a TNF antagonist that overcomes the above described drawbacks.
There is further a need to improve the efficacy of TNF antagonists in the treatment of inflammation, diseases associated with inflammation and other diseases, by preventing bacterial translocation and by inducing systematic regulatory cells.